NL8100808A - 2-AMINO-3-HYDROXY (PHENYL) METHYLPHENYL ACETIC ACIDS, THEIR ESTERS AND AMIDES. - Google Patents

Description

VO 153¼ -1-.

2-amino-3-1hydroxy (phenyl) methyl] phenylacetic acids, bunesters and esters

The invention relates to 2-amino-3- [hydroxy (phenyl) -aetbyl] phenylacetic acids, their metal salts, hydrates thereof, bun esters and bunsmids, which have pharmacological activity in warm-blooded animals and pharmaceutical methods and preparations, wherein these compounds are used.

2-amino-3- (5 and 6) benzoylphenylacetic acids, bun esters, metal salts and hydrates thereof with anti-inflammatory properties are described in U.S. Pat. Nos. 4,045,516 and 4,126,635-

South African Patent 68/4682 discloses benzoyl-10-phenylacetamide which may contain a range of substituents in unspecified positions of the enyl group. None of the particularly preferred compounds therein are aminophenylacetamides.

The compounds of the invention are 2-amino-3- [hydroxy- (phenyl) methyl] phenylacetic acids, their metal salts, hydrates thereof, their esters and amides of the general formula 1 of the formula sheet, wherein R 1 is a hydrogen atom or a lower alkyl group, 2 3 4 R an OH group, an OM group, an O-lower alkyl group or a group -HR R, 3 4 R and R each a hydrogen atom, a lower alkyl group, a cycloalkyl group, phenyl group , a lower alkyl phenyl group, a lower alkoxy group, a halogen atom or a trifluoromethyl group or R 4 R and R together with the adjacent nitrogen atom a heterocyclic group, M a pharmaceutically acceptable cation or a fraction thereof, when the cation is polyvalent, 25 Am a primary amino group or a dimethylamino group, X represents a hydrogen or halogen atom, a lower alkyl group or a trifluoromethyl group and Y represents a hydrogen or halogen atom, a lower alkyl group, a lower alkoxy group, a trifluomethyl group or a methylthic group, while 30 n ee n is an integer from 1-3 and, when n is greater than 1, the different groups Y may be the same or different, while the formula also includes hydrates of all of the above compounds.

In the above-mentioned definition of the symbols and in the passages hereinafter 8100808-2- in the description, "lower alkyl" is understood to mean a straight or branched chain alkyl group of 1-8 carbon atoms, such as a methyl, ethyl, propyl , isopropyl, butyl, sec.butyl, tert.butyl, amyl, isoamyl, hexyl, heptyl, or octyl group.

5 'By low alkoxy' is meant an -O-low alkyl group.

By "cycloalkyl" in this specification is meant a cyclic alkyl group having 3-9 carbon atoms, for example, a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methylcyclohexyl or cycloheptyl group.

In this specification, "halogen atom" is understood to mean a fluorine, chlorine, broc, or iodine atom, and preferably a fluorine, chlorine, or bromine atom.

By "heterocyclic group" is meant a group, such as a morpholino, pyrrolidino, piperidino, piperazino, or the like group.

By "pharmaceutically acceptable cation" is meant any metal cation that is acceptable for internal administration to warm-blooded animals, for example sodium, potassium, calcium, magnesium, zinc, copper and aluminum ones and water of hydration. Preferably a sodium ion is used.

Anti-inflammatory treatment was demonstrated in laboratory animals with a modification of the Evans-Blue Carrageenan Pleura!

Effusion Assay of Sancilio, L. F., J. Pharmacol. Exp. Ther. 168, 199-201 (1969).

The compounds can also be used as a fever suppressant, as an analgesic and to prevent platelet clumping. Preferred compounds for their anti-inflammatory activity are of the formula 1, wherein 1 R is a hydrogen atom or a methyl group, p 30 R is an OH, OM or O-lower alkyl group,

Am a NH 3 or dimethylamino group, X a hydrogen or halogen atom, a lower alkyl group or a trifluoromethyl group, Y a hydrogen or halogen atom, a lower alkyl group, a lower alkoxy-35 group, a trifluoromethyl group or a -S-low alkyl group, M is a pharmaceutically acceptable cation or a fraction thereof, when the cation is polyvalent and 8100808-3n represent an integer of 1-3.

It is an object of the invention to provide new 2-amino-3- [hydroxy- (phenyl) methyl] phenylacetic acids, their metal salts, hydrates, amides and esters.

Another object is to provide a new method to treat living animal bodies, especially mammals, to relieve inflammation, using these 2-amino-3- [hydroxy- (phenyl) methyl] phenylacetic acids and said derivatives thereof.

Said acids, salts, esters and amides, with the exception of the exceptions listed below, may be prepared by preparing the earbonyl portion of the 2-amino-3-benzoylphenyl acetic acids used as starting material, their salts, esters and amides. reduction, as needed, by hydrogenation with palladium on carbon or by reduction with sodium borohydride according to the equation A of the formula sheet, wherein the various substituents have the above meaning. When in 2 compounds of formula 2 R. is an O 1 group then hydrogenation with palladium on carbon causes cyclization. In that case you can. use sodium borohydride in twice the stoichiometric amount.

Preferably, however, R cm is put in a salt (OM) or its equivalent 20 in a basic solution and then hydrogenated with hydrogen and palladium on charcoal, followed by gentle acidification with a weak acid, such as acetic acid, as shown by equation B of the formula sheet. Heating above 30 ° C results in loss of hydroxyl groups to form a phenylmethyl derivative.

Compounds of formula 1, wherein X or Y is a halogen atom, can be prepared from the corresponding precursor of formula 2, by reduction with sodium borohydride because hydrogenation with palladium on carbon will cause loss of halogen.

When Y is a -S-low-alkyl group in the compounds of Formula 2, hydrogenation results in loss of the -S-low-alkyl group.

When the Y is a -S-lower-alkyl group, the corresponding compounds of formula 1 are preferably prepared starting from a compound of formula 1, wherein Y is a fluorine atom, as shown in reaction scheme C, in which the different substituents represent the have the above meaning.

2

Compounds of the invention, wherein R is an OE group, can be prepared according to Reaction Scheme D.

8 1 0 0 8 0 3 -h-

The formulas 1A-TG are all covered by formula 1.

2

The starting materials of formula 2, wherein R is an OH group, OM group, or -O-lower alkyl group and Am is an amino group or dimethylamino group, may be prepared as described in U.S. Patent No. K,0. ^ 5-576.

. . . 2 3 k.

Starting materials of formula 2, wherein R is a group -NR R, may be prepared as described in patent application 0J8,860 of September 26, 1979 according to the reaction scheme E of the formula sheet, wherein the different substituents have the previously mentioned meaning 10, but wherein Y is not a -S-lower-alkyl group and R 1 is a lower-alkyl group or a phenyl group. The compounds of formula 2b, in which Am is a dimethylamino group, can be prepared by compounding compounds of formula 2b, in which Am = cm with formaldehyde and cyanoborohydride. The preparation of the compounds of formula IIb and intermediates therefor are illustrated in preparations 1-29.

Preparation 1 h- [2- (methylthioacetyl)] morpholine.

A mixture of 1 (0.2 g (0.3 mole) ethyl methyl thioacetate and 1 g (1.5 mole) morpholine was refluxed for 70 hours.

20

Fractional distillation under reduced pressure gave k5 g (86%) of a product with a boiling point 10U-105 ° C at 0.05 mm of mercury on the second distillation.

Analysis:. Calcd for C 7 H 15 NO 5 S, C, 7.98; H, 7 ^ 8; N, 7.99 Found: C, Vf, 55; H, 7.59; H, 8.18 25. .

Preparation 2 2-methylthio-N-methyl acetamide.

A mixture of 13 g (1.0 mole) ethyl methyl thioacetate and 310 g (10.0 mole) methylamine was heated in a bomb at 150 ° C for 72 hours. The excess amine and the ethanol formed were distilled off and the remaining thin syrup was distilled to yield 112 g (9 W of the desired acetamide as a colorless liquid, bp 76-78 ° C at 0.1 mm mercury pressure.

Analysis: Calculated for C 4 H 10 STOS: C 1 (0.31; H, 7.61; 1.11 .75. Found: C, 39.78; Η, 7, β9; N, 11.88. 3 2-methylthio-U, U-dimethylacetamide.

A mixture of 13 g (1.0 mole) ethyl methyl thioacetate and 360 g (8.0 mole) dimethylamine was heated in a bomb for 90 hours at 150 ° C.

8100808 -5-

The oveinate and the voided ethanol were distilled off and the residue was distilled to yield 129 g (97%) of the desired acetamide as a clear, colorless liquid, bp 76-77 ° C at 0.5 am mercury pressure.

Analysis: Calculated for C 1 H NOS: C, 1 * 5.08; H, 8.32; N, 10.51 Found: C, 1 * 3.88; H, 8.1 * 1; N, 10.60

Preparation h 2- (2-propylthio) acetamide.

To a mixture of 1 * 6.7 g (0.5 mole) of 2-chloroacetamide in 200 ml of absolute ethanol was added in a slow stream a solution of 38.1 g (0.5 mole) of 2-propanethiol in 100 ml absolute ethanol and 50 g of aqueous sodium hydroxide. The mixture was heated under reflux for 1 hour and then filtered. The filtrate was evaporated under reduced pressure. The residue was dissolved in methylene chloride and the solution was dried over magnesium sulfate. The mixture was filtered and the filtrate was evaporated again. On standing, the syrupy residue crystallized. Recrystallization from isopropyl ether gave 59.0 g (89 $) of white plates, mp 52-5 ** ° C.

Analysis: Calculated for C 1 H HOS: C, 1 * 5.08; H, 8.32; ½, 10.51 Found: C, 1 * 5.05; H, 8.32; 10, 10.55 3 preparation 5 2- (1-propylthio) acetamide.

Using the same procedure as in Preparation 1 *, but with an equal molar amount of 1-propanethiol instead of 2-propanethiol, 61.2 g (92%) of the desired acetamide were obtained. The white crystals had a melting point of 29.5-51.0 ° C.

Analysis: Calculated for C 1 H HOS: C, 1 * 5.08; H, 8.32; H, 10.51

Found: C, 1 * 1 *, 97; H, 8.21 *; 10.1 * 0

Preparation 6 1 2 3 4 5 6 8100808 2-amino-3-benzoyl-5-chloro-a- (methylthio) phenylacetamide.

2

To a cold solution (-70 ° C) of 12.77 g (0.055 mol) of 3 2-amino-5-chlorobenzophenone in 300 ml of methylene chloride was added 6.0 g (0.0552 mol) of tert under a nitrogen atmosphere .butyl hypochlorite 5 in 20 ml of methylene chloride. After stirring for an additional 15 minutes, a suspension 6 of 5.8 g (0.055 mol) a- (methylthio) acetamide in 150 ml of methylene chloride was added. The mixture was stirred at -65 ° C for 1 hour. 5.6 g of triethylamine (0.055 mol) was added to this and the solution was allowed to warm to room temperature. The reaction mixture was extracted with several portions of water and the organic layer was dried with magnesium sulfate. The solution was evaporated in vacuo to about 200 ml and the product crystallized as a yellow solid, mp 173.5-174.5 ° C. Yield 6.86 g (37.358).

Analysis: Calculated for C 7 H 15 G 5 SCl: C, -57.40; H, 4.52; H, 8.37 Found: C, 57.38; H, 4.50; N, 8.51

Preparation 7 2-amino-3-benzoyl-a- (methylthio) phenylacetamide, 10, In a cold solution (-70 ° V) of 19.7 g (0.10 mol) 2-amino-benzophenone in 300 ml methylene chloride a solution of 11.5 g (0.10 mol) of 95% t-butyl hypochlorite in 30 ml of methylene chloride was added under a nitrogen atmosphere, followed after 10 minutes by a solution of 10.5 g (0.1 mol) methylthioacetamide in 300 ml of tetrahy-15 drofuran. During these additions, the temperature was kept at a maximum of -55 ° C. After an additional hour at -60 ° C, the mixture was allowed to warm to room temperature and the precipitate formed was filtered off.

The precipitate was suspended in 200 ml of methylene chloride and 11 g (0.11 mol) of triethylamine were added. The mixture was stirred for 5 minutes. The solution was then washed twice with 100 ml of water each time and the organic phase was then dried with magnesium sulfate and evaporated under reduced pressure. The residue was washed with diethyl ether and dried, yielding 13.0 g (43 $) of light yellow powder, mp 153-155 ° C.

Analysis: Calculated for C 1 H 15 N 5 S: C, 63.98; H, 5.37; H, 9.33

Found: C, 63.61 *; H, 3.59; H, 9.25

Preparation 8 2-amino-3- (4-chlorobenzoyl) -a- (phenylthio) phenyl acetamide.

To a cold solution (-70 ° C) of 34.6 g (0.15 mol) 2-amino-4'-30-chlorobenzophenone in 500 ml methylene chloride was added 17.3 g (0.15 mol) 95% t Butyl hypochlorite was added, followed after 10 minutes by a solution of 25.0 g (0.15 mol) of phenylthioacetamide in 400 ml of tetrahydrofuran, which solution was added over 20 minutes. During this addition, the temperature was kept at a maximum of -6k ° C.

For 2 hours, 20 g (0.2 mol) of triethylamine were added and the mixture was allowed to warm to room temperature. The mixture was evaporated to dryness and the residue was partitioned between water and methylene chloride. The material 8100808-7 which did not dissolve in either phase was filtered off, washed with 20% 1s aqueous ethanol and dried, yielding 36 g (61 µl) of light yellow powder, mp 189-191 ° C.

Analysis: Calculated for C 1 H N N O O SC 1: C, 63.55; H, ,32; H, 7.06. Found: C, 63.73; H, b, 36; N, 7.16

Preparation 9 U- (2- (2-amino-> 3 <-ben2oylphenyl) -2- (methylthio) acetyl) morpholine.

To a cold solution (-65 ° C) of 9.9 g (0.05 mol) 2-amino-benzophenone and 8.8 g (0.05 mol) k- (a-methylthio) aetylmorpholine in 200 ml 10 methylene chloride a solution of 5.8 g (0.05 mol) of 95 µl of tert-butyl hypochlorite in 20 ml of methylene chloride was added dropwise. After an additional hour at -60 ° C, 5.1 g (0.05 mol) of triethylamine was added and the mixture was allowed to warm to room temperature. The solution was washed twice with 100 ml of water, dried with magnesium sulfate and evaporated to dryness under reduced pressure. The residue was chromatographed on 600 g of silica gel, eluting first with diisopropyl ether and then with 10 # acetone in diisopropyl ether. The eluate was evaporated to dryness, the residue was dissolved in 150 ml of ethanol and the solution was poured into 100 ml of water. The undissolved solid was recrystallized from diethyl ether and dried. Yield 12.3 g (62¾) of yellow crystals, mp 119-121 ° C.

Analysis: Calculated for C 6i +, 8U; H, 5.99; N, 7.56

Found: C, 65.01; H, 5.99; N, 7.57

Preparation 10 25-amino-3-benzoyl-5-chloro-a - [(1-chlorophenyl) thio] phenylacetamide.

To a cold solution (-70 ° C) of 20 g (0.0863 mol) 2-amino-5-chlorobensophenone in 500 ml methylene chloride was added in a nitrogen atmosphere a solution of 9-8 g (0.088 mol) tert. butyl hypochlorite in 50 ml of methylene chloride. After stirring for 15 minutes, a solution of 17.35 g (0.0863 mol) a- (U-chlorophenylthio) acetamide in 500 ml of a 50/50 mixture of tetrahydrofuran and methylene chloride was added. The mixture was stirred at -70 ° C for 2 hours, 8.72 g (0.0863 mol) of triethylamine was added and the solution was allowed to warm to room temperature over 2 hours with stirring. The reaction mixture was extracted with several portions of water and the organic layer was dried with magnesium sulfate. The solution was evaporated to about 500 ml. Then 500 ml of methylene chloride was added to precipitate the product, which after 8100808 -8- filtration and drying weighed 16.62 g {kk-, 7%). The yellow solid melts at 198-200 ° C.

Analysis: Calculated for 6 ^ 2 ^ 2 ^^ ½; 58, 8; Sj 3.7 ^; N, 6, ^ 9

Found: C, 58.14; H, 3.77; N, 6.67. Preparation 11 2-amino-3-benzoyl-5-chloro-α- (phenylthio) phenylacetamide.

To a cold solution (-70 ° C) of 80.72 g (0.3 ^ 9 mol) of 2-amino-5-chlorobenzophenone in 1.5 l of methylene chloride, 39.1 g (0.360 mol) of tert-butyl hypochlorite were added under nitrogen. added in 100 ml of methylene chloride. After stirring for 10 minutes, a solution of 59.1 g (0.35% mol) a- (phenyl-thio) acetamide in 1.5 l of tetrahydrofuran was added. The mixture was stirred at 1.25 hours. -65 ° C, 37.5 g (0.371 mol) triethylamine was added and the solution was allowed to warm to room temperature. The reaction mixture was extracted with a few portions of water and the organic layer was dried with anhydrous sodium sulfate. The solution was evaporated in vacuo to precipitate a yellow solid which, after recrystallization from acetonitrile, yielded a yellow crystalline solid, mp 190-191 ° C (decomposition).

Analysis: Calculated for C 14 H 25 NgOgSCl: C, 63.55; H, U, 32; N, 7.06. Found: C, 63.62; H, ,29; N, 7.08

Preparation 12 2-amino-3-benzoyl-a- (phenylthio) phenylacetamide.

In the same manner as in preparation 11, but with an equal molar amount of 2-aminobenzophenone in place of 2-amino-5-chloro-25-benzophenone, the desired acetamide was obtained in 57% yield. After recrystallization from a mixture of methylene chloride, diethyl ether and hexane, the compound had a melting point of 153-15 ° C

Analysis: Calculated for C 21 H 18 N 2 O 2 S: C, 69.59; H, 5.01; N, 7.73 Found: C, 69.33; H, 5.00; N, 7.76 Preparation 13 2-amino-3-benzoyl-a- (methylthio) -N-methylphenylacetamide.

A solution of 29.6 g (0.15 mole) of 2-aminobenzophenone in 350 ml of methylene chloride was cooled to -70 ° C and a solution of 17.9 g (0.15 mole) of 2-methylthio-N-methyl acetamide in 20 ml of methylene chloride 35 was added. A solution of 17.2 g (0.15 mol) of 95% t-butyl hypochlorite in 30 ml of methylene chloride was added dropwise to the mixture kept at -70 ° C. The temperature was held at 8100808-9 ° C -65 ° C for 1.5 hours and then 15 * 1 g (0 * 15 mol) of triethylamine was added quickly. The solution was allowed to warm to room temperature and then the solution was washed with water. The organic solution was evaporated to dryness and the residue crystallized on mixing with isopropyl ether.

The solid was recrystallized from isopropanol to yield 31 g (>> 5%) of yellow needles, mp 11 + 9.0-150 ° C.

Analysis: Calculated for C 15.6gOgS: C 6, 9, 9; H, 5 * 77; 8.91 Found: C, 65.2 * +; 5, 5.83; N, 8.99

Preparation 14 10 2-amino-3-benzoyl-α- (methylthio) -H, Ν-dimethylphenyl acet and amide.

A solution of 29.6 g (0.15 mole) of 2-aminobenzophenone in 350 ml of methylene chloride was cooled to -70 ° C to which was added 20.0 g (0.15 mole) of 2-methylthio-ir, ϊϊ-dimethylacetamide added. A solution of 17.2 g (0.15 mol) of 95% tert-butyl hypochlorite in 30 ml of methylene chloride was added dropwise to the mixture at -70 ° C. The temperature was held at -65 ° C for 1.5 hours and then 15.1 g (0.15 mol) of triethylamine was added quickly. The solution was allowed to warm to room temperature and the solution was washed with water. The organic solution was evaporated and the residue crystallized on mixing with isopropyl ether. The solid was recrystallized from isopropanol to yield 39 * 8 g (81 $) of bright yellow crystals, mp 153-155 ° C.

Analysis: Calculated for gE ^ H ^ O ^ S: C, 65.83; H, 6.14; N, 8.53

Found: C, 65.87; H, 6.15; N, 8.52. Preparation 15 2-amino-3- (1 + -fluorobenzyl} -a- (n-propylthio) phenylacetamide.

A solution of 21.5 g (0.1 mol) V-fluoro-2-aminobenzophenone in If-OO ml of methylene chloride was cooled to -T0 ° C and 11.5 g (0.1 mol) 95 # tert-butyl hypochlorite was added while the temperature was kept at -66 ° C.

A solution of 13.3 g of 2-n-propylthioacetamido in 50 ml of methylene chloride was added to this solution over 10 minutes.

The solution was stirred between -65 ° C and -T0 ° G for 1 hour and then the solution was allowed to warm to 0 ° C. At that temperature, 10.2 g of 35 (0.1 mol) triethylmine was added. The solution was stirred for an additional 10 minutes and then washed with water. The organic solution was dried with magnesium sulfate. Evaporation to dryness under reduced pressure, the residue was crystallized from isopropanol and dried, yielding 19.5 g (56%) of yellow crystals, m.p. 100-120 ° C.

Analysis: Calculated for C 1 2 3 4 SF: C, 62, U1; H, 5.53; N, 8.09 Found: C, 62.3U; H, 5.58; U, 8.0¼ 5 Preparation 16

Prepared in the same manner as in Preparation 8: 2-amino-3- (2-fluorobenzoyl) -a- (phenylthio) phenyl acetamide, 2-amino-3- (b -tr if fluoromethyl benzoyl) -a- (f enylthio) enylac edami de, 2-amino-3- (2, k-dichlorobenzoyl) -a- (phenylthio) phenylacetamide, and 10 2-amino-3- (2, U-difluorobenzoyl) -a- (phenylthio ) enylacetamide.

Starting from the phenylthioacetamide, tert-butyl hypochlorite and 2-amino-2'-fluorobenzophenone, 2-amino-k'-trifluoromethyl-benzophenone, 2-amino-2 ', 1' -dichlorobenzophenone, and 15 2-amino-2! , U'-difluorobenzophenone.

Preparation 17 2-amino-3-benzoyl-5 "chloro-ct- (methylthio) -N-methylphenylacetamide. To a solution of 38.3 g (0.166 mol) of 2-amino-5-chlorobenzophenone in 1 L of methylene chloride cooled at -70 ° C, 18.05 g (0.167 mol) of t-butyl hypochlorite was added under nitrogen. The solution was stirred for 15 minutes and then a solution of 20.3 g (0.171 mol) of 2-methylthio-U-methylacetamide in 100 ml of methylene chloride was added.

The solution was stirred at -70 ° C for 2 hours and then 25 ml of triethylamine was added. The solution was allowed to warm to room temperature with stirring and then the solution was extracted with water and the organic layer was dried with magnesium sulfate. The volume of the solution was reduced to about 500 ml, ether was added and the solution was placed in a refrigerator at about 0 ° C overnight.

A solid crystallized and was separated and dried in high vacuum at 50 ° G for about an hour. The weight was 31.56 g (5 ^ 6 $) and the melting point 170-171 ° C.

Analysis: Calculated for C 1 H 15 IgSCl: C, 58.53; H, 1) -, 91; N, 8.03 Found: C, 56.68; H, U, 91; N, 8.13

Preparation 18 35 3-Benzoyl-2- (N-methylamino) -a- (methylthio) phenylacetamide.

Using equimolar amount of 2-N-methyl-aminobenzophenone instead of 2-aminobenzophenone in preparation 7 gives 8100808-11 the above-mentioned compound.

Preparation 19 2-amino-3-benzoyl-5-chlorophenylacetamide,

A mixture of 21.3 g (0.0639 mol) 2-amino-3-benzoyl-5-chloro-a-5 (methylthio) phenylacetamide and an excess of raney nickel were added in a mixture of 900 ml absolute ethanol 200 ml dimethyl ? omamide stirred at room temperature ^ 5 minutes. The mixture was filtered by removing cellite to remove the raney nickel. The solvent was removed in vacuo to leave a yellow solid, which melted at 213.5-215.5 ° C (decomposition) after recrystallization.

Analysis: Calculated for C ^^ H ^^ 2 ^ 3 ^: ^ 2 ^ 0; H, --5.5 -5 H, 9.70

Found: C, 62.35; H, J +, 58; H, 9.7¾

Preparation 20 2-amino-3-benzoyl-phenylacetamide.

15 With stirring, 80 g of wet raney nickel was added to a solution of 9.7 g (0.032 mol) of 2-aminc-3-benzoyl-a- (methylthio) -phenylacetamide in 100 ml of tetrahydrofuran (washed three times with water and three drops). with tetrahydrofuran). After 10 minutes, the raney nickel was filtered from the mixture and the substrate was evaporated in vacuo. The residue 20 was crystallized from isopropanol to yield 6.0 g (73%) of yellow needles with melting point 178.5-180.0 ° C.

Analysis: Calculated for Ο ^ Η ^ Ν ^ Ο ^: C, 70.85; H, 5.55; H, 11.02 Found: C, 70.53; H, 5.53; H, 11.0¾

Preparation 21 2-Amino-3- (t-chlorobenzoyl) phenylacetamide.

While stirring, add to a solution of 28.5 g (0.077 mol) 2-amino-3 - (^ - chlorobenzoyl) -a- (phenylthio) phenylacetamide in 1 1 tetrahydrofuran 230 g wet Raney nickel (washed three times with water and three times with tetrahydrofuran). After 15 minutes, the mixture was filtered and the filtrate was evaporated to dryness under reduced pressure to obtain 17.5 g (8 µg) of a yellow crystalline solid.

Recrystallization from isopropanol and recrystallization twice from absolute ethanol yielded yellow needles mp 212-215 ° C,

Analysis: Calculated for C 14 H 14 H Cl: C 62 62 U; H, U, 5 ^; H, 9.70. Found: C, 62.76; H, fc, 5O; H, 9.83

Preparation 22 U- (2- (2-amino-3-benzoylphenyl) acetyl) morpholine.

While stirring, a solution of 18.5 g (0.05 mol) of U- [2- (2- 8100808-12-amino-3-benzoylphenyl) -2- (methylthio) acetyl] morpholine in 300 ml of tetrahydrofuran was added 150 g of wet Raney nickel added. After 15 minutes, the mixture was filtered and the filtrate was evaporated to dryness under reduced pressure. After recrystallizing the residue from isopropanol, 13.3 g (82%) of bright yellow crystals, mp 156.5-158.5 ° C, were obtained. Analysis: Calculated for Ο ^ Η ^ ΪΓ ^ Ο ^: c »TO, 35; H, 6.22; H, 8.64 Found: C, 70.24; H, 6.21; H, 8.63

Preparation 23 2- am ino-3-benzoyl-H-m ethylphenylac edamide e.

A solution of 22.5 g (0.072 mol) 2-amino-3-benzoyl-a- (methyl thio) -H-methylphenylacetamide in 400 ml tetrahydrofuran was treated for 10 minutes with 160 g wet Raney nickel (washed trially with water and drianally with tetrahydrofuran). The mixture was filtered and the filtrate was evaporated to dryness. The residue was crystallized from iso-15 propanol to obtain 17.2 g (89%) of yellow needles.

Melting point 145-146 ° C.

Analysis: Calculated for C16H16N2 ° 2: 71'71'62; E> 6'01; 119 10> kk

Found: C, 71.76; H, 6.05; H, 10.52

Preparation 24 2-Amino-3-benzoyl-H, H-dimethylphenyl acetate amide.

A solution of 33.0 g (0.1 mol) 2-amino-3-benzoyl-α- (methylthio) -N, H-dimethyl If eny laceetamide in 500 ml tetrahydrofuran was treated for 10 minutes with 240 wet Raney nickel ( washed trially with water and trially with tetrahydrofuran). The mixture was filtered and the filtrate was evaporated to dryness. The residue was crystallized from isopropanol to yield 27.2 g (96%) of yellow needles. Melting point 123-124 ° C. Analysis: Calculated for C H N N: C, 72.32; H, 6.43; H, 9.92

Found: C, 72.34; H, 6.42; N, 9.98

Preparation 2-Amino-3- (4-fluorobenzyl) -phenylacetamide.

A solution of 24.2 g (0.07 mol) 2-amino-3- (4-fluorobenzoyl-a- (n-propylthio) phenylacetamide) in 300 ml tetrahydrofuran was treated with 250 g wet Raney nickel (washed trially with water and drianally with tetrahydrofuran) The mixture was stirred for one hour and then filtered 35 The filtrate was evaporated in vacuo and the residue was recrystallized from 95% ethanol to yield 14.8 g (78%) of yellow needles. mp 184-186 ° C.

3100808 -13-

Analysis: Calculated τοογ C5 66.17; Ξ, ^, 81; IT, 10.29

Found: C, 66.32; H, US81; N, 10, ^ 8

Preparation 26

In the same manner as in "preparation 2 were obtained: 5 2-amino-3- (2-fluorobenzoyl) phenylacetamide, 2-smino-3- (2,2-dichlorobenzoyl) phenylacetamide, 2-amino-3- (2 , 1 * -difluorobenzoyl) phenylacetamide, and 2-amino-3- (U-trifluoromethylbenzoyl) phenylacetamide Starting from: 10 2-amino-3- (2-fluorobenzoyl) -a- (phenylthio) phenylacetamide, 2-amino- 3- (2, ^ - dichlorobenzoyl) -a- (phenylthio) phenylacetamide, 2-amino-3- (2, V-difluorobenzoyl) -a- (phenylthio) phenylacetamide, and 2-amino-3- ( k-trifluoromethylbenzoyl) -ct- (phenylthio) phenylacetamide Preparation 27 15 2 = amino-3-benzoyl-5-chloro-W-methylphenylacetamide.

A solution of 28.33 g (0.08l mol) of 2-amino-3-benzoyl-5-chloro-a- (methylthio) -1-methyl acetamide in 1 l of tetrahydrofuran was treated with excess Raney at room temperature for 2 hours. nickel. The solution was filtered through cellite. The remaining Raney nickel was washed with acetone and the washing liquid was filtered. The combined organic filtrates were dried over magnesium sulfate and then evaporated to about 300 ml. An excess of ether was added and the solution was allowed to stand at room temperature for 1 hour and then in a refrigerator overnight. The precipitated yellow solid weighed 20.9 µg ($ 85.68) after drying and had a melting point of 1T9-180 ° C,

Analysis: Calculated for C 14 H 15 IT 2 Cl: C 63, 8; H, h, 99; Ν ', 9.25 Found: C, 63, kh; S, k, 99; N, 9.27

Preparation 28 3-Benzoyl-2- (N-methylamino) phenylacetamide.

When in preparation 20, 3-benzoyl-2- (N-methylamino) -a- (methylthio) phenylacetamide is used instead of 2-amino-3-benzoyl-a- (methyl-thio) phenylacetamide, one obtains the above mentioned connection. Preparation 29 3-Benzoyl-2- (N, T-dimethylsmino} phenylacetamide.

A solution of 12.7 g (0.05 mol) of 2-amino-3-benzoylphenylacetamide in 150 ml of acetonitrile was treated four times with 16 ml (0.2 mol) of 37% formaldehyde, 6.0 hg (0. 1 mole) of sodium cyanoborohydride and 2 ml of 8100808 µl-glacial acetic acid, stirring for 15 minutes after each treatment. Finally, the mixture was poured into dilute NaOH solution and extracted three times with diethyl ether. The ether extracts were combined, dried over magnesium sulfate and evaporated to dryness. The product was isolated by column chromatography.

The invention is illustrated by the following examples: Example I

2-amino-3- [hydroxy (phenyl) methyl] phenylacetic acid hydrate (1: 1).

25 ml of 3N sodium hydroxide, followed by 0.285 g (0.0075 mol) of sodium borohydride, was added to a solution of 2 g (0.0072 mol) of sodium 2-10 amino-3-benzoyl phenylacetate hydrate in 25 ml of water with stirring.

The voided yellow solution was stirred for 18 hours during which time the color of the solution became considerably lighter. The solution was filtered, cooled and slowly neutralized with glacial acetic acid. The white precipitate obtained weighed 1.3 g (65%); the substance sintered at 115 ° C and melted at 160 ° C.

Analysis: Calculated for C 10 H 10 O: C 65. H 6 6.22; N, 5> 09 Found: C, 65.13; H, 6.21; II, 5.08

Example II 1 2 3 4 5 6 7 8 9 10 11 12 8100808 20. Sodium salt of 2-amino-3- [hydraxy (phenyl) methyl] phenylacetic acid,

A solution of 1 h-58 g (0.05 mol) of sodium salt of 2-amino-3-benzoylphenylacetic acid monohydrate in 250 ml of tap water was hydrogenated with 10% palladium on charcoal overnight at room temperature. The mixture was filtered through cellite and the resulting filtrate was evaporated to dryness under reduced pressure. The residue was crystallized by evaporation 3 times with 50 ml of absolute ethanol each time to give a white solid. The solid was recrystallized from a mixture of methanol and diethyl ether and then from ethanol and water, yielding 6% g (53%) white solid, mp 273 ° C.

7

Analysis: Calculated for C 10 H 10 NO: C 6 ^ 51; H, 0.05; N, 5 »02 15 14 3 8

Found: C, 6U, 37; Ξ, 5 »07; N, 5 »03 9

Example III

2-amino-5-chloro-3- [hydroxy (phenyl) m ethyl] phenylacetic acid.

11

To a solution of 12.5δ g (0.0U mol) 12 sodium salt of 2-amino-3-benzoyl-5-chlorophenyl acetate in 100 ml water was added with stirring 100 ml 3N sodium hydroxide solution, followed by 1.6 g ( (Ok mol) sodium borohydride. The mixture was stirred for 3 hours, until the -15 solution turned bright orange. The solution was then neutralized with acetic acid (foaming). A precipitate was formed adding excess acetic acid and this precipitate was filtered off, washed with water and dried. A cream-colored solid was obtained (10.2 g) 5 (19%), m.p. 13 ° C (decomposition).

Analysis: Calculated for C 4 H 10 CUTO: C, 61.76; H, U, 8U; W, U. 80 Found: C, 61.69; H, U, 81; W, U, 76

Example IV

Sodium salt of 2-amino-3- [hydroxy (U-chlorophenyl) methyl] phenylacetic acid hydrate (U: 1).

A mixture of 9> 0 g (0.029 mol) sodium salt of 2-amino-3- (U-chlorobenzoyl) phenyl acetate monohydrate in 200 ml water and 100 ml 2% solid ITaOH solution was filtered through cellite and the filtrate was treated with 1.1 g (0.3 mol) sodium borohydride. The mixture was stirred at room temperature for 3 hours for 15 hours and again filtered through celite.

The filtrate was acidified with acetic acid (foams). The white solid formed was filtered off and washed with water. The solid was suspended with stirring in a solution of 1.1 g (0.03 mol) of ffaOH in 150 ml of water. The solution was filtered and the filtrate 20 titrated to pH 8.5 with 15 # hydrochloric acid. After standing overnight at room temperature, the mixture was filtered through cellite and the filtrate was evaporated under reduced pressure. The residue was crystallized with absolute ethanol to give a white solid, which could be recrystallized from water and wooted 1.2 g (kl%) after drying.

Saelt point 138 ° C (decomposition).

Analysis: Calculated for C ^ H ^ CUTO ^ ifa. H, U, 28; N, h, k2

Found: C, 56.62; Ξ, U, 28y H, U, Uo

Example V

When the sodium salt of 2-smino-3-benzoyiphenylacetic acid dihydrate is used in the process of Example 1, the same molar amounts of the following substances are used: Hatrium-2-aminc-3-benzoyl-5-chlorophenyl acetate,

Habrium-2-smino-3- (U-chlorobenzoyl) phenyl acetate hydrate, Ethyl-2-amino-3- (U-chlorobenzoyl) phenyl acetate, Sodium 2-amino-3- (U-fluorobenzoyl) phenyl acetate,

2-Amino-3- (3, U-dichlorobenzoyl) phenyl acetate, 2-Amino-3- (3-methoxy-U-chlorobenzoyl) phenyl acetate, 8100808

"V

-16- then 2-amino-3- [hydroxy (phenyl) ethyl] -5-chlorophenylacetic acid, 2-amino-3- [hydroxy (il-chlorophenyl) methyl] phenylacetic acid, ethyl-2 -amino-3- [hydroxy (if-chlorophenyl) methyl] phenyl acetate, 5 2-amino-3- [hydroxy (U-fluorophenyl) methyl phenylacetic acid,

2-amino-3- [hydroxy (3, U-di-chlorophenyl) methyl] phenylacetic acid. 2-amino-3- [hydroxy (3-methoxy-4-chlorophenyl) methyl] phenylacetic acid. Example VI

When the molar amounts of 2-amino-3-benzoyl-phenyl-acetic acid monohydrate of the following substances are used in the process according to Example 2, ΕΓ atrium-2-am ino-3 -b etc. oy1-5-methoxypheny lac et aat ses quihydrate, Ethyl-2-amino-3-b etc olylphenyl acetate,

Methyl 2-amino-3-benzoylphenyl acetate, methyl 2-dimethylamino-3-benzoylf enyl acetate,

Sodium 2-amino-3-benzoyl-α-methylphenyl acetate hydrate, Potassium 2-amino-3-benzoyl phenyl acetate hydrate,

Sodium 2-amino-3- (U-methoxybenzoyl) phenyl acetate, 20 ethyl-2-amino-3- [hydroxy (phenyl) m ethyl] phenyl acetate are obtained,

Methyl-2-amino-3- [hydroxy (phenyl) methyl] phenyl acetate,

Methyl-2-dimethylamino-3- [hydroxy (phenyl) methyl] phenyl acetate, 2-amino-3- [hydroxy (phenyl) methyl] phenylacetic acid, 2 = amino-3- [hydroxy (phenyl) m ethyl] phenylacetic acid 2-amino-3- [hydroxy (1-with hoxyphenyl) methyl] phenyl acetic acid.

Example VII -

When the molar amounts of the sodium salt of 2-amino-3-benzoylphenylacetic acid are used instead of the following substances in the process according to example 1: 2-amino-3-benzoyl-5-chlorophenylacetamide, 2-am.ino- 3-benzoyl-phenylacetamide, k- [2- (2-amino-3-benzoylphenyl) acetyl] morpholine, 2-amino-3-benzoyl-N-methylphenylacetamide, 2-amino-3-benzoyl-N dimethylphenylacetamide, 2-amino-3- (U-fluorobenzoyl) phenylacetamide, 2-amino-3- (2-fluorobenzoyl) phenylacetamide, 2-amino-3- (2,1 * -di chlorobenzoyl) phenylacetamide , 8100808 -1? - 2-amino-3- (2, U-difluorobenzoyl) phenylacetamide, 2-amino-3- (^ -trifluoromethylb etc oy 1) phenyl amide, 2-amino-3-benzcyl- 5-chloro-N-methylphenylacetamide, 3-benzoyl-2- (N, N-dimethylamino) phenyl amide, 5 then 2-smino-3- [hydroxy (phenyl) methyl] -5-chlorophenylacet amide is obtained , 2-amino-3- [hydroxy (phenyl) methyl] phenylacetamide, k- {2- {2-amino-3- [hydroxy (phenyl) m ethyl]} acetyl} morpholine, 2-amino-3- [hydraxy (f eny l) methyl] -N-methylphenylacetamide, 2-amino-3- [hydroxy (phenyl) methyl] -Ν, Ν-dimethylphenylacetamide, 2-aminc-3- [hydroxy (U-fluorophenyl) methyl] phenylacetamide, 2-amino-3- [hydroxy (2-fluorophenyl) methyl] phenylacetamide, 2-amino-3- [hydroxy (2, k-dichlorophenyl) methyl] phenylacetamide, 2-amino-3- [hydroxy (2, 1 + -difluorophenyl) methyl] phenyl acetamide, 2-amino-3- [hydroxy (U-trifluoromethylphenyl) methyl] phenylacetamide,

2-smino-3- [hydroxy (phenyl) methyl] -5-chloro-N-methylphenylacetamide, 2- (N, N-dimethylamino) -3- [hydroxy (phenyl) methyl] phenylacetamide. Example VIII

Sodium scut of 2-amino-2- (hydroxy (U-methylthiophenyl) methyl] -20 phenylacetic acid.

The said compound is prepared by first preparing an ethanol solution of 2-amino-3-Khydroxy- (U-fluorophenyl) methyl] -phenylacetic acid with an equivalent amount of sodium hydroxide and refluxing this solution with an excess of methyl-mercaptide after which the compound can be isolated in the usual manner.

Example IX

2-amino-3- [hydrxy (U-methylthiophenyl) methyl] phenylacetamide.

The above compound can be prepared by refluxing in ethanol 2-amino-3- [hydroxy (Fluorophenyl} methyl] -f enylacetamide) with an ethyl acetate sodium chloride and isolating the product in the usual manner.

Formulation and administration;

The invention also relates to new pharmaceutical preparations containing the compounds of the invention as active ingredient. Effective amounts of any of the above pharmacologically active compounds can be administered to a living animal body in a variety of ways, e.g., orally in the form of capsules or tablets, parenterally in the form of sterile solutions or suspensions and in some cases intravenously in the form of sterile solutions.

When preparing the new preparations according to the invention, the active ingredient is incorporated in a suitable carrier, for example a pharmaceutical carrier. Suitable pharmaceutical carriers useful according to the invention include starch, gelatin, glucose, magnesia carbonate, lactose, maltose, and the like. Liquid preparations are also included in the invention and suitable liquid carriers are: ethanol, propylene glycol, glycerol, corn syrup, and the like.

The pharmacologically active compounds can be effectively administered in a unit dose of between 0.1 and 2β mg or more, depending on the size of the animal concerned. For example, a large animal, such as a horse, may contain tablets containing 500-1000 mg of the active ingredient. The unit dose can be administered an appropriate number of times per day, so that the daily dose can range from 0.3-50 mg. 5-25 mg. per unit dose. seems very beneficial.

It is only necessary that the active agent be administered in an effective amount, i.e., such that an effective dose is obtained, which is compatible with the dosage form used. The correct individual dose and the correct daily dose can of course only be determined using the usual medical principles and under the supervision of a doctor or veterinarian.

The active substances according to the invention can be combined with other pharmacological, active substances or with buffering agents, acid-binding agents, and the like for administration, and the amount of active substance in the preparations can be varied within wide limits. Below are some examples of preparations prepared according to the invention.

/ 1. Capsules.

Capsules were prepared with resp. 5 mg, 25 mg and 50 mg active substance / capsule. For larger amounts of active substance, the amount of lactose can be adjusted if desired.

8100808 -19-

Typical mixture Tan de Per capsule • capsules______ mg_

Active substance 5.0

Lactose 296.7 5 Starch 129.0

Magnesium stearate 1 *, 3

Total 1 * 35.0 mg

Other capsule formulation and preferably contain a larger dose of active ingredient, for example, as follows:

Per capsule Ingredients m ... Active substance 25.0 Lactose 306.5 Starch 99.2 Magnesium stearate> .3 Total 1 * 35.0 mg 10 15

In either case, the selected active substance is first mixed uniformly with the lactose, starch and magnesium stearate, after which the mixture is used to fill capsules.

20 2. Tablets.

A typical tablet formulation containing 3.0 mg of active substance / tablet follows. This formulation can also be used with other amounts of active ingredient by adjusting the amount of dicalcium phosphate.

25 Per tablet mg (1) Active substance 5.0 (2) Corn starch 13.6 (3) Corn starch (pasta) 3.1 * (¾) Lactose 79.2 (5) Dicalcium phosphate 68.0 (6) Calcium stearate 0, 9 170.1 8100808 -20-

Mix components 1, 2, k and 5 · Process 3 to a 10% paste in water. Granulate the mixture with the starch paste and sieve the wet mass through a sieve with 2, b mm openings. Dry the wet granules and sieve them through a sieve with 1.1) mm openings. Mix the dried 5 granules with the calcium stearate and beat into tablets.

3. Sterile $ 2 injection solutions.

3 Per cm 2 0 mg 0.5 $ g / cm3 q.s.

Active ingredient

Preservative, for example, chlorobut anol

Water for injections

Prepare a solution, filter it, fill it in ampoules, melt it and sterilize it by heating.

Various modifications and equivalents of the methods are apparent to those skilled in the art, without, therefore, limiting the invention.

8100808

Claims (21)

1. A compound of formula 1, wherein Η ** a hydrogen atom or a lower alkyl group, R ^ an OH, OM, -O-lower alkyl or -WK ^, 3 UR and R each a hydrogen atom, a lower alkyl group, a cycloalkyl-5 group, a phenyl group, which may be substituted by lower alkyl, a lower alkoxy group, a halogen atom or a trifluoromethyl group or also together with the adjacent nitrogen atom a heterocyclic group, M a pharmaceutically acceptable cation or equivalent if the cation is polyvalent, 10 Am a primary aminc group (-M ,,), or a dimethylamino group, X a hydrogen or halogen atom, a lower alkyl group or a trifluoromethyl group, ï a hydrogen or halogen atom, a lower alkyl group, a lower alkoxy group, a trifluoromethyl group, or a methylthio group and n represent an integer of 1-3, while when n is greater than 1, the different groups Y may be the same or different, as well as hydrates of such compounds. A compound according to claim 1, characterized in that the compound is 2-amino-3- [hydroxy (phenyl) methyl] phenylacetic acid. Compound according to claim 1, characterized in that it is 2-amino-3- [hydroxy (phenyl) methyl] phenylacetic acid hydrate (1: 1). A compound according to claim 1, characterized in that it is the sodium trim salt of 2-amino-3- [hydroxy (phenyl) methyl] phenyl acetic acid. Prohibition according to claim 1, characterized in that it is 2-amino-5-25 J chlorcor-3- [hydroxy (phenyl) methyl] phenylacetic acid. A compound according to claim 1, characterized in that it is 2-amino-3- [hydroxy (U-chlorophenyl) methyl] phenyl acetic acid. A compound according to claim 1, which consists of the sodium salt of 2-amino-3- [hydroxy (4-chlorophenyl) methyl] phenylacetic acid hydrate (¼: 1). 30 A method of alleviating inflammation in a living animal body by internally administering an effective amount of a compound as described in any one of claims 1-7. 9. Process according to claim 8, characterized in that the compound is 2-amino-3- [hydroxy (phenyl) methyl] phenylacetic acid. Process according to claim 8, characterized in that 2-amino-3- [hydroxy (phenyl) methyl] phenylacetic acid hydrate (1: 1) is used. 35 8 100 808 -22- Process according to claim 8, characterized in that the sodium salt of 2-amino-3- [hydroxy (phenyl) methyl] phenylacetic acid is used. 12. Process according to claim 8, characterized in that 2-amino-5-chloro-3- [hydroxy (phenyl) methyl] phenylacetic acid is used. Process according to claim 8, characterized in that 2-amino-3- [hydroxy (1-chloro-phenyl) methyl] phenylacetic acid is used. 1U. Process according to claim 8, characterized in that the (^: 1) hydrate of the sodium salt of 2-amino-3- [hydroxy (h-chlorophenyl) methyl] phenylacetic acid is used. Pharmaceutical preparation with anti-inflammatory action, characterized in that the active ingredient contains a compound of one of the compounds described in claim 1. Preparation according to claim 15, characterized in that the compound is 2-amino-3- [hydroxy (phenyl) methyl] phenylacetic acid. Preparation according to claim 15, characterized in that the compound is 2-amino-3- [hydroxy (phenyl) methyl] phenylacetic acid hydrate (1: 1). Preparation according to claim 15, characterized in that the compound is the sodium salt of 2-amino-3- [hydroxy (phenyl) ethyl] phenylacetic acid. Preparation according to claim 15, characterized in that the compound 20 is 2-amino-5-chloro-3- [hydroxy (phenyl) methyl] phenylacetic acid. Preparation according to claim 15, characterized in that the compound is 2-amino-3- [hydroxy (U-chlorophenyl) methyl] phenylacetic acid. 21. A composition according to claim 15, characterized in that the compound is the (U: 1) hydrate of the sodium salt of 2-amino-3- [hydroxy (U-chlorophenyl) methyl] phenylacetic acid. 22. A compound according to claim 1, characterized in that 1 R is a hydrogen atom or a methyl group, 2 R is an OH, OM or -O-lower alkyl group, Am is a or dimethylamino group, 30. is a hydrogen or halogen atom, a lower alkyl group or a trifluoro-methyl group, Y a hydrogen or halogen atom, a lower alkyl or alkoxy group, a trifluoromethyl group or a -S-low-alkyl group, M a pharmaceutically acceptable cation or an equivalent thereof, when the cation is polyvalent and n represent an integer of 1-3. 810080